Familial Adenomatous Polyposis Panel: (APC) Sequencing and Deletion/Duplication, (MUTYH) 2 Mutations

Background Information for Familial Adenomatous Polyposis Panel: (APC) Sequencing and Deletion/Duplication, (MUTYH) 2 Mutations:

Characteristics of APC-associated Polyposis: Familial Adenomatous Polyposis (FAP): Development of hundreds to thousands of adenomatous colonic polyps beginning in early adolescence; lifetime risk for cancer is 100 percent. Additional findings may include dental anomalies, polyps of the gastric fundus and duodenum, and congenital hypertrophy of the retinal pigment epithelium (CHRPE).
Attenuated FAP: Fewer colonic adenomatous polyps (average of 30), which are more proximally located and cancer generally occurs at a later age; lifetime risk for cancer is 70 percent.
Gardner syndrome: Multiple colonic adenomatous polyps along with osteomas, desmoid tumors, and soft tissue tumors.
Incidence:  Less than 1 percent of colorectal cancer cases.
Inheritance:  Autosomal dominant.
Penetrance:  Greater than 99 percent in untreated individuals.
Causes:  Pathogenic APC gene mutations.
Clinical Sensitivity: Approximately 95 percent for classic FAP and less than 30 percent for attenuated FAP.
Methodology: Bidirectional sequencing of the APC coding region and intron-exon boundaries.  Multiplex ligation-dependent probe amplification (MLPA) to detect large APC coding region deletions or duplications. 
Analytical Sensitivity and Specificity: 99 percent.
Limitations: Diagnostic errors can occur due to rare sequence variations. APC regulatory region and deep intronic mutations will not be detected. Deletion/duplication breakpoints will not be determined. This assay is not designed to detect somatic variants associated with malignancy. Interpretation of this test result may be impacted if the patient has had an allogeneic stem cell transplantation.

Characteristics of MUTYH-associated Polyposis (MAP): Development of colonic polyps (10-100) with the age of diagnosis occurring in the third decade or older.
Incidence:   Less than 1 percent of colorectal cancer cases.
Inheritance: Autosomal recessive.
Penetrance: Greater than 99 percent in untreated individuals.
Causes: Pathogenic biallelic MUTYH gene mutations.
Clinical Sensitivity: 85 percent of MUTYH mutations in Caucasians.
Methodology: Targeted testing for the MUTYH mutations c.494A>G(Y165C) and c.1145G>A (G382D) by PCR and bidirectional sequencing.
Analytical Sensitivity and Specificity: 99 percent.
Limitations: Diagnostic errors can occur due to rare sequence variations. Mutations in the MUTYH gene, other than Y165C and G382D, are not evaluated.